Project Summary There is an urgent need for agents that slow or arrest the progressive course of AD. BAN2401 and aducanumab, antibodies partially targeting soluble A? oligomers, have shown efficacy in late-stage clinical trials, validating amyloid targeting in AD. ALZ-801, an oral agent that selectively inhibits the formation of A? oligomers, is an improved prodrug formulation of tramiprosate. ALZ-801 and its active agent, tramiprosate, showed favorable preclinical and clinical safety that supports a regulatory submission. Alzheon is developing ALZ-801 as a disease-modifying treatment for AD patients who are homozygous for the ?4 allele of the apolipoprotein E gene (APOE4). Tramiprosate was evaluated in two placebo-controlled 78-week Phase 3 trials, which enrolled 2025 patients with Mild to Moderate AD (Mini-Mental State Examination, MMSE, scores of 16-26). Co-primary efficacy outcomes in both trials were: Alzheimer?s Disease Assessment Scale-Cognitive Subscale (ADAS-cog) and Clinical Dementia Rating-Sum of Boxes (CDR-SB). In the completed Phase 3 trial, efficacy outcomes did not achieve significance in the overall study population of 1052 subjects. In a protocol-specified analysis, there was clinically meaningful efficacy in APOE4 carriers (approximately 60% of all subjects). Additional analyses revealed a gene dose effect, with APOE4/4 homozygotes showing most benefit versus placebo (ADAS-cog ~3.0 points, nominal p<0.05) on top of symptomatic therapy. This benefit was greater in the Mild APOE4/4 patients (MMSE 22-26) who showed dose dependent efficacy, with the high dose group showing 5.5 points improvement on ADAS-cog, nominal p = 0.0003. The strong efficacy of tramiprosate/ALZ-801 in APOE4/4 patients can be explained by their high rate of amyloid positivity (98%) on amyloid PET imaging versus 60% in noncarriers. APOE4/4 AD patients have also been shown to have a higher burden of A? oligomers than noncarriers. APOE4/4 patients therefore represent an AD phenotype that is enriched with A? oligomers and most likely to benefit from the anti-oligomer effect of ALZ-801. Tramiprosate showed favorable long-term safety in ~1600 AD patients; the most common adverse events were mild to moderate nausea and vomiting. In healthy elderly and AD subjects, ALZ-801 showed improved gastrointestinal tolerability and improved pharmacokinetics compared to tramiprosate. We plan to conduct a Phase 3 clinical trial to evaluate the efficacy of ALZ-801 in APOE4/4 patients with Early AD (MMSE 22-30) using ADAS-cog as the primary clinical outcome. We will also evaluate the effects on an MRI imaging biomarker (hippocampal volume), on plasma and CSF biomarkers of neurodegeneration, and the correlations of biomarkers with clinical outcomes. These results can confirm the efficacy of ALZ-801 as a disease-modifying drug by stabilizing cognition, and potentially decreasing brain atrophy in this population. ALZ-801 has received FDA Fast Track status, and positive data can support submission for regulatory approval and inform future AD trial designs.